Compositions and methods for the treatment of meibomian gland dysfunction

ABSTRACT

Described herein are compositions and methods for the treatment of meibomian gland dysfunction. Said compositions and methods comprise keratolytic agents, such as salicylic acid, selenium disulfide, or the like. Topical administration of said compositions to the eyelid margin or surrounding areas provides therapeutic benefit to patients suffering from meibomian gland dysfunction.

CROSS REFERENCE

This application claims the benefit of U.S. Provisional Application No.62/065,716, filed Oct. 19, 2014, which is incorporated by referenceherein in its entirety.

BACKGROUND OF THE INVENTION

Meibomian gland dysfunction, or MGD, is a leading contributor of dry eyesyndrome and is often characterized by a keratinized obstruction of theterminal duct of the meibomian gland.

SUMMARY OF THE INVENTION

Prior to the methods and formulations described herein, there were nopharmacological agents useful for the treatment of MGD, including forthe removal of the keratinized obstruction of the meibomian gland, orfor the prevention of further keratinized obstruction of the meibomiangland. Current technology for removing keratinized obstruction of themeibomian gland is limited to physical removal methods, some of whichare quite painful to the patient.

As such, described herein, are methods and formulations for treatingMGD. In one embodiment is provided a method for treating meibomian glanddysfunction in a patient in need thereof, comprising topicallyadministering to the patient a composition that reaches the eyelidmargin of the patient, wherein the composition comprises atherapeutically-effective amount of at least one keratolytic agent in anophthalmically-acceptable carrier. In some embodiments, the keratolyticagent is benzoyl peroxide, coal tar, dithranol, salicylic acid, seleniumdisulfide, alpha-hydroxy acid, urea, lactic acid, sodium thioglycolate,zinc pyrithione, or zinc L-pyrrolidone carboxylate. In some embodiments,the keratolytic agent is salicylic acid or selenium disulfide. In someembodiments, the keratolytic agent is selenium disulfide. In someembodiments, the concentration of the selenium disulfide in thecomposition is between about 0.1% to about 10%. In some embodiments, thekeratolytic agent is salicylic acid. In some embodiments, thecomposition is topically administered to the patient until thekeratinized obstruction is relieved. In some embodiments, thecomposition is topically administered to the patient periodically afterrelieving the keratinized obstruction. In some embodiments, the topicaladministration is a single administration. In some embodiments, thetopical administration is a periodic administration. In someembodiments, the periodic administration is once a day. In someembodiments, periodic administration is two times a day. In someembodiments, the composition for topical administration is a semi-solid.In some embodiments, the composition for topical administration ishomogenous. In some embodiments, the composition for topicaladministration is a dispersion. In some embodiments, the composition fortopical administration is hydrophilic. In some embodiments, thecomposition for topical administration has an oleaginous base. In someembodiments, the ophthalmically-acceptable carrier comprises at leastone ophthalmically-acceptable excipient. In some embodiments, theadministration of the composition results in enhanced meibum production.

In one embodiment is provided a method for treating meibomian glanddysfunction in a patient in need thereof, comprising topicallyadministering to the patient a composition that reaches the eyelidmargin of the patient, wherein the composition consists of atherapeutically-effective amount of a keratolytic agent in anophthalmically-acceptable carrier. In some embodiments, the keratolyticagent is salicylic acid or selenium disulfide. In some embodiments, thekeratolytic agent is selenium disulfide. In some embodiments, theconcentration of the selenium disulfide in the composition is betweenabout 0.1% to about 10%. In some embodiments, the administration of thecomposition results in enhanced meibum production. In some embodiments,the composition for topical administration is homogenous. In someembodiments, the composition for topical administration is a dispersion.In some embodiments, the composition for topical administration ishydrophilic. In some embodiments, the composition for topicaladministration has an oleaginous base. In some embodiments, theophthalmically-acceptable carrier comprises at least oneophthalmically-acceptable excipient.

In one embodiment are methods for treating MGD by administering ameibomian gland opening pharmacological agent which allows for theopening of the meibomian gland (at least in part), the passage of thekeratinized obstruction (at least in part), and/or the prevention ofsubsequent keratin obstructions (at least to the extent that suchobstructions lead to meibomian gland dysfunction) within the meibomiangland. In one embodiment, the formulation comprises atherapeutically-effective amount of the meibomian gland openingpharmacological agent. In one further or alternative embodiment, theformulation comprises an additional therapeutic agent that is not ameibomian gland opening pharmacological agent. In one further oralternative embodiment, the formulation comprises an additionalmeibomian gland opening pharmacological agent. In one alternativeembodiment, the formulation does not include any additional therapeuticagents other than an additional meibomian gland opening pharmacologicalagent. In one alternative embodiment, the formulation consists only of asingle meibomian gland opening pharmacological agent and no othertherapeutic agents. In any of the aforementioned embodiments, theformulation optionally comprises an ophthalmically-acceptable carrier.In one further embodiment, the ophthalmically-acceptable carriercomprises an ophthalmically-acceptable excipient.

In one aspect, the methods and formulations described herein includepharmacological agents that are useful for the treatment of MGD in asubject in need. In some embodiments, the formulations described hereinare applied to the eyelid margin of a patient in need. In someembodiments, multiple applications of the formulations are required.

In some embodiments, the eye is shielded, at least in part, to preventthe pharmacological agents from contacting the eye of the subject inneed. Further described are kits comprising a formulation describedherein along with a device that shields the eye from contact with theformulation.

The methods and formulations described herein include an active agent ata therapeutic level, that by itself, or in combination with othercomponents, acts to open (at least in part) an obstructed meibomiamgland or prevent (at least in part) further obstruction of the meibomiangland. Further, such active agent is formulated or applied, such that itis acceptable to the surface of the eye (i.e. not causing undueirritation or disruption to the epithelial surface of the eye), andwithout compromising lipid producing cells in contact with theformulation.

In some embodiments, the formulation is applied for a duration andfrequency that is acceptable and practical to the physician or patientadministering the agent. For example, a physician applies a formulationdescribed herein weekly or twice a week for several weeks to induceopening (at least in part) of the obstruction and the patient applies adifferent formulation on a daily basis, or the patient uses a morepotent formulation on a daily basis for several weeks and then,subsequently uses a less potent formulation of a daily basis thereafter.

In some embodiments the method of application varies, depending on theconcentration of the active agent and/or the severity of the MGD to betreated, including but not limited to shielding the ocular surface. Inother embodiments, the method of application or formulation, is variedto enhance the penetration or residency time on the target tissue toenhance the treatment effect. In other embodiments, the method ofapplication or formulation, is varied to enhance the penetration orresidency time on the target tissue to minimize the amount of timenecessary. In other embodiments, the method of application orformulation, is formulated (e.g., viscosity enhancement and/orskin-adhesiveness) to increase contact with the target tissue whileminimizing contact with non-target tissues, including the eye, and thuslimit or reduce any undesired collateral activity.

In certain aspects of the methods and formulations described herein, theconcentration of the active agent, and the components of co-formulationare optimized to deliver the minimum effective concentration of activeagent to achieve the therapeutic benefit while minimizing any ocularirritation or disruption, or irritation or disruption to surroundingocular tissues. The method and formulation described herein are meansfor removal (at least in part) of the keratinized obstruction of themeibomian gland, or to prevent further keratinized obstruction (at leastin part) of the meibomian gland.

The formulations include at least one meibomian gland openingpharmacological agent. In some embodiments the meibomian gland openingpharmacological agent is a keratolytic and/or keratoplastic agent. Insome embodiments the keratolytic and/or keratoplastic agent within theformulation is the active agent responsible for opening or maintainingthe patency of the meibomian gland canal.

In some embodiments agents having primarily keratolytic effect are used.In some embodiments agents having primarily keratoplastic effect areused. In some embodiments agents having both keratolytic andkeratoplastic effect are used. In some embodiments the keratolyticand/or keratoplastic agent enhances lipid production in the meibomianglands. In some embodiments the meibomian gland opening pharmacologicalagent is an anesthetic. In some embodiments the meibomian gland openingpharmacological agent is an anti-inflammatory agent. In some embodimentsthe meibomian gland opening pharmacological agent is an anti-oxidantagent. In some embodiments the meibomian gland opening pharmacologicalagent is an inhibitor of prostaglandin synthethase. In some embodimentsthe meibomian gland opening pharmacological agent is a lipooxygenase orcyclooxygenase enzyme.

In one aspect described herein are methods for treating meibomian glanddysfunction in a patient in need thereof comprising topicallyadministering to at least the non-mucosal epithelial side of the eyelidmargin of the patient a composition comprising atherapeutically-effective amount of at least one meibomian glandobstruction opening pharmacological agent applied in anophthalmically-acceptable manner or formulation. In one aspect of themethods and formulation described herein, the formulation includes apharmaceutical excipient.

In some embodiments, the meibomian gland opening pharmacological agentis a keratolytic and/or keratoplastic agent chosen from benzoylperoxide, coal tar, dithranol, salicylic acid, selenium disulfide,inorganic selenium compounds such as selenium disulfide, SeCl₄, Na₂SeO₃,organo-selenium compounds such as Ebselen(2-phenyl-1,2-benzisoselenazol-3(2H)-one) or its analogues,alpha-hydroxy acid, urea, lactic acid or sodium thioglycolate. In someembodiments, the keratolytic and/or keratoplastic agent is chosen frombenzoyl peroxide, coal tar, dithranol, salicylic acid or seleniumdisulfide. In some embodiments, the keratolytic and/or keratoplasticagent is salicylic acid or selenium disulfide. In some embodiments, thekeratolytic and/or keratoplastic agent is salicylic acid. In someembodiments, the keratolytic and/or keratoplastic agent is seleniumdisulfide. In some embodiments, the at least one keratolytic and/orkeratoplastic agent is salicylic acid. In some embodiments, the at leastone keratolytic and/or keratoplastic agent is selenium disulfide. Insome embodiments, the salicylic acid is present from about 0.1% to about30%. In some embodiments the selenium disulfide is present from about0.1% to about 10%.

In some embodiments, the meibomian gland opening pharmacological agentis an anesthetic chosen from an aminoamide local anesthetic and/or anaminoester local anesthetic. In one embodiment, the aminoamide localanesthetic or the aminoester local anesthetic is present at aconcentration between about 4% and about 80%. In one embodiment, theaminoamide local anesthetic or the aminoester local anesthetic ispresent at a concentration between about 6% and about 60%. In oneembodiment, the aminoamide local anesthetic or the aminoester localanesthetic is present at a concentration between about 8% and about 50%.In one embodiment, the aminoamide local anesthetic or the aminoesterlocal anesthetic is present at a concentration between about 10% andabout 40%. In one embodiment, the aminoamide local anesthetic or theaminoester local anesthetic is present at a concentration between about12% and about 45%. In one embodiment, the aminoamide local anesthetic orthe aminoester local anesthetic is present at a concentration betweenabout 14% and about 40%. In one embodiment, the formulation comprisesmore than one local anesthetic.

In some embodiments, topical administration of the compositioncomprising at least one meibomian gland opening pharmacological agentoccurs twice a week. In some embodiments, topical administration of thecomposition comprising at least one meibomian gland openingpharmacological agent occurs every other day. In some embodiments,topical administration of the composition comprising at least onemeibomian gland opening pharmacological agent occurs every day. In someembodiments, topical administration of the composition comprising atleast one meibomian gland opening pharmacological agent occurs severaltimes a day.

In some embodiments, the composition for topical administration is aliquid or a semi-solid. In some embodiments, the composition for topicaladministration is an emulsion semi-solid. In some embodiments, thecomposition for topical administration is a cream. In some embodiments,the composition for topical administration is an ointment. In someembodiments, meibomian gland opening pharmacological agent is suspendedwithin the composition. In some embodiments, the composition for topicaladministration is a lotion. In some embodiments, the composition fortopical administration is a gel.

DETAILED DESCRIPTION OF THE INVENTION

Prior to the methods and formulations described herein, there were nopharmacological agents useful for the treatment of MGD, including forthe removal of the keratinized obstruction of the meibomian gland, or toprevention of further keratinized obstruction of the meibomian gland.

Current technology for removing keratinized obstruction of the meibomiangland is limited to painful physical removal methods. As such, describedherein, are methods for treating MGD by administering a meibomian glandopening pharmacological agent which allows the passage of thekeratinized obstruction, and also preventing the buildup of subsequentkeratin obstructions within the meibomian gland. The meibomian glandopening pharmacological agents described herein include agents for acutetherapies, for use, e.g., by a physician or other trained specialist,and agents for chronic therapies, e.g., either by a physician or othertrained specialist, or by the patient. Certain meibomian gland openingpharmacological agents are provided herein; further provided herein aremethods and assays for identifying further meibomian gland openingpharmacological agents (e.g., by testing the relative keratolyticactivity of a potential agent, such as examples 1 and 2).

Meibomian Gland

The meibomian glands are large sebaceous glands located in the eyelids,and unlike skin, are unassociated with hair. The meibomian glandsproduce the lipid layer of the tear film that protects it againstevaporation of the aqueous phase. The meibomian gland orifice is locatedon the epithelial side of the lid margin, and is only a few hundredmicrons from the mucosal side. The glands are located on both upper andlower eyelids, with higher amounts of the glands on the upper eyelid. Asingle meibomian gland is composed of clusters of secretory acini thatare arranged circularly around a long central duct and connected to itby short ductules. The terminal part of the central duct is lined by aningrowth of the epidermis that covers the free lid margin and forms ashort excretory duct that opens as an orifice at the posterior part ofthe lid margin just anterior to the mucocutaneous junction near theinner lid border. The oily secretion composed of lipids is synthesizedwithin the secretory acini. The lipid secretion is a liquid at near bodytemperature and is delivered to the skin of the lid margin as a clearfluid, called “meibum.” It forms shallow reservoirs on the upper andlower lid margins, and consists of a complex mixture of cholesterol,wax, cholesteryl esters, phospholipids, with small amounts oftriglycerides, triacylglycerols, and hydrocarbons. The separatemeibomian glands are arranged in parallel, and in a single rowthroughout the length of the tarsal plates in the upper and lower lids.The extent of the glands corresponds roughly to the dimensions of thetarsal plates.

The term “keratinized obstruction” as used herein refers to a blockageof the meibomian gland, regardless of the location of the blockage. Insome embodiments, the blockage is complete, whereas in otherembodiments, the blockage is partial. Regardless of the degree ofblockage, such keratinized obstruction leads to meibomian glanddysfunction. In some embodiments, the keratinized obstruction iscomposed of keratinized material and lipids. In some embodiments, thekeratinized obstruction is a blockage at the meibomian gland orifice andexcretory duct. In some embodiments, the keratinized obstruction iscaused by keratinization of the epithelium at the lid margin andmeibomian gland. In certain instances, the keratin obstruction isinfluenced by the migration or aberrant differentiation of stem cells.In some embodiments, the keratinized obstruction results in reduceddelivery of oil to the lid margin and tear film, and stasis inside themeibomian gland that causes increased pressure, resultant dilation,acinar atrophy, and low secretion. In certain instances, keratinizationof the meibomian gland causes degenerative gland dilation and atrophy.

Meibomian Gland Dysfunction (MGD)

The term, “meibomian gland dysfunction,” as used herein, refers tochronic, diffuse abnormality of the meibomian glands, that ischaracterized by terminal duct obstruction or qualitative orquantitative changes in the glandular secretion, or both. MGD may resultin alteration of the tear film, eye irritation symptoms, inflammation,or ocular surface disease. The most prominent aspects of MGD areobstruction of the meibomian gland orifices and terminal ducts andchanges in the meibomian gland secretions.

MGD is a leading contributor of dry eye syndrome. The occurrence of dryeye syndrome is widespread and affects about 20 million patients in theUnited States alone. Dry eye syndrome is a disorder of the ocularsurface resulting from either inadequate tear production or excessiveevaporation of moisture from the surface of the eye. Tears are importantto corneal health because the cornea does not contain blood vessels, andrelies on tears to supply oxygen and nutrients. Tears and the tear filmare composed of lipids, water, and mucus, and disruption of any of thesecan cause dry eye. An inadequate amount of lipids flowing from themeibomian glands as caused by a keratinized obstruction, may causeexcessive evaporation, thereby causing dry eye syndrome.

MGD is not synonymous with posterior blepharitis, which describesinflammatory conditions of the posterior lid margin. MGD may causeposterior blepharitis, but MGD may not always be associated withinflammation or posterior blepharitis. MGD also refers to functionalabnormalities of the meibomian gland, while “meibomian gland disease,”describes a broad range of meibomian gland disorders, that includesneoplasia and congenital disease. Clinical signs of MGD includemeibomian gland dropout, altered meibomian gland secretion, and changesin lid morphology.

In some embodiments, altered meibomian gland secretion is detected byphysically expressing the meibomian glands by applying digital pressureto the tarsal plates. In subjects without MGD, the meibum is a pool ofclear oil. In MGD, both the quality and expressibility of the expressedmaterial is altered. The altered meibum is also known as meibomianexcreta and is made up of a mixture of altered secretions andkeratinized epithelial material. In MGD, the quality of expressed lipidvaries in appearance from a clear fluid, to a viscous fluid containingparticulate matter and densely opaque, toothpaste-like material. Themeibomian orifices may exhibit elevations above surface level of thelid, which is referred to as plugging or pouting, and is due toobstruction of the terminal ducts and extrusion of a mixture ofmeibomian lipid and keratinized material.

Obstructive MGD is characterized by all or some of the following: 1)chronic ocular discomfort, 2) anatomic abnormalities around themeibomian gland orifice (which is one or more of the following: vascularengorgement, anterior or posterior displacement of the mucocutaneousjunction, irregularity of the lid margin) and 3) obstruction of themeibomian glands (obstructive findings of the gland orifices by slitlamp biomicroscopy (pouting, plugging or ridge), decreased meibumexpression by moderate digital pressure).

Current methods for assessing and monitoring MGD symptoms include, butare not limited to patient questionnaires, meibomian gland expression,tear stability break up time, and determining the number of patentglands as seen by digital expression.

In some embodiments, the symptoms of a patient are assessed by askingthe patient a series of questions. Questionnaires allow the assessmentof a range of symptoms associated with ocular discomfort. In someembodiments, the questionnaire is the SPEED questionnaire. The SPEEDquestionnaire assesses frequency and severity of a patient's dry eyesymptoms. It examines the occurrence of symptoms on the current day,past 72 hours and past three months. A SPEED score is tallied based onthe patient's answers to the questions, to give a range of severity ofthe patient's symptoms. The SPEED questionnaire includes questions suchas the following: 1) what dry eye symptoms are you experiencing, andwhen do they occur? 2) how frequently do you experience dryness,grittiness, or scratchiness in your eyes? 3) how often do you experiencesoreness or irritation of the eyes? 4) how often do you experienceburning or watering of the eyes? 5) how often do you experience eyefatigue? and 6) how severe are the symptoms?

Meibomian gland expressibility is optionally determined to assess themeibomian gland function. In normal patients, meibum is a clear to lightyellow oil. Meibum is excreted from the glands when digital pressure isplaced on the glands. Changes in meibomian gland expressibility are onepotential indicator of MGD. In some embodiments, during expression,quantifying the amount of physical force applied during expression ismonitored in addition to assessing lipid volume and lipid quantity.

Tear stability break up time (TBUT) is a surrogate marker for tearstability. Tear film instability is a core mechanism in dry eye and MGD.Low TBUT implies a possibility of lipid layer compromise and MGD. TBUTis optionally measured by examining fluorescein breakup time, as definedas the time to initial breakup of the tear film after a blink.Fluorescein is optionally applied by wetting a commercially availablefluorescein-impregnated strip with saline, and applied to the inferiorfornix or bulbar conjuctiva. The patient is then asked to blink severaltimes and move the eyes. The break up is then analyzed with a slit lamp,a cobalt blue filter, and a beam width of 4 mm. The patient isinstructed to blink, and the time from upstroke of the last blink to thefirst tear film break or dry spot formation is recorded as ameasurement.

Other methods for assessing MGD symptoms, include but are not limitedto, Schirmer test, ocular surface staining, lid morphology analysis,meibography, meibometry, interferometry, evaporimetry, tear lipidcomposition analysis, fluorophotometry, meiscometry, osmolarityanalysis, indices of tear film dynamics, evaporation and tear turnover.

Current treatments for MGD include lid warming, lid massage, lidhygiene, lid expression and meibomian gland probing. Pharmacologicalmethods, prior to those described herein, have not been used.

Lid hygiene is considered the primary treatment for MGD and consists ofthree components: 1) application of heat, 2) mechanical massage ofeyelids and 3) cleansing the eyelid. Eyelid warming procedures improvemeibomian gland secretion by melting the pathologically alteredmeibomian lipids. Warming is achieved by warm compresses or devices.Mechanical lid hygiene includes the use of scrubs, mechanical expressionand cleansing with various solutions of the eyelashes and lid margins.Lid margins are optionally also cleansed with hypoallergenic bar soap,dilute infant shampoo or commercial lid scrubs. Physical expression ofmeibomian glands is performed in a physician's office or is performed bythe patient at home. The technique varies from gentle massage of thelids against the eyeball to forceful squeezing of the lids eitheragainst each other or between a rigid object on the inner lid surfaceand a finger, thumb, or rigid object (such as a glass rod, Q-tip, ormetal paddle) on the outer lid surface. The rigid object on the innerlid surface protects the eyeball from forces transferred through theeyelid during expression and to offer a stable resistance, to increasethe amount of force that is applied to the glands.

Eyelid warming is limited because the warming melts the lipids, but doesnot address movement of the keratinized material. Further, eyelidwarming induces transient visual degradation due to corneal distortion.Mechanical lid hygiene is also limited because the force needed toremove an obstruction can be significant, resulting in significant painto the patient. The effectiveness of mechanical lid hygiene is limitedby the patient's ability to tolerate the associated pain during theprocedure. Other treatments for MGD are limited.

Physical opening of meibomian glands obstruction by meibomian glandexpression is an acceptable method to improve meibomian gland secretionand dry eye symptoms. In addition probing of the meibomian gland canalhas been used to open the obstructed canal. Both methods, expression andprobing, are limited, however, by the pain induced by the procedure, thepossible physical insult to the gland and canal structures and theirshort lived effect estimated at days and weeks. Therefore, methods areneeded to improve patient comfort, which will not cause harm to themeibomian glands and canals, that will reduce the dependency on frequentoffice visits and improve secretion of meibum.

Meibomian Gland Opening Pharmacological Agents

Keratolytic and/or Keratoplastic Agents

The keratolytic and keratoplastic agents described herein are useful ineither as an acute therapy (e.g., by a trained specialist or physician)or as a chronic therapy (e.g., in the hands of a patient, oralternatively, by a trained specialist or physician). The agents aretested, in certain embodiments, using the assays and methods describedherein (e.g., as described in the examples).

One embodiment provides a method for treating MGD in a patient in needthereof comprising topical administration of a composition comprising ameibomian gland opening pharmacological agent, wherein the meibomiangland opening pharmacological agent is a keratolytic agent orkeratoplastic agent. In some embodiments, the meibomian gland openingpharmacological agent is a keratolytic agent chosen from allantoin,benzoyl peroxide, inorganic selenium compounds such as seleniumdisulfide, SeCl₄, Na₂SeO₃, organo-selenium compounds such as Ebselen(2-phenyl-1,2-benzisoselenazol-3(2H)-one) or its analogues, coal tar,dithranol, salicylic acid, selenium disulfide, alpha-hydroxy acid, urea,lactic acid, sodium thioglycolate, zinc pyrithione, or zincL-pyrrolodione carboxylate. In some embodiments the keratolytic agent isnot retinoic acid.

It is important that the agents used to open the meibomian gland haveminimal undesired side effects, such a gland atrophy and/or interferencewith lipid production in the gland. Thus, in some embodiments agentswith such undesired side effects are not included within the scope ofthe formulations described herein. By way of example, retinoic acid, ora retinoic acid derivative may cause gland atrophy or interfere withlipid production in certain patients or at certain concentrations orfrequency of use, and as such, in some embodiments retinoic acid, or aretinoic acid derivative are not used in the formulations and methodsdescribed herein.

In certain embodiments, a mild or weak keratolytic and/or keratoplasticagents is used in the methods and formulations described herein, e.g.,with subjects that produce low levels of keratin. Such mild or weakkeratolytic and/or keratoplastic agents are optionally used in amaintenance therapy setting. Mild or weak keratolytic and/orkeratoplastic agents include lower concentrations of active keratolyticand/or keratoplastic agents, as well as keratolytic and/or kerotoplasticagents that have low inherent activity (as determined, e.g., by themethods described herein). In certain embodiments, the mild or weakkeratolytic and/or keratoplastic agents is not boric acid.

One embodiment provides a method for treating meibomian glanddysfunction in a patient in need thereof, comprising topicallyadministering to the patient a composition that reaches the eyelidmargin of the patient, wherein the composition comprises atherapeutically-effective amount of at least one keratolytic agent in anophthalmically-acceptable carrier. In one embodiment, the keratolyticagent is benzoyl peroxide. In another embodiment, the keratolytic agentis coal tar. In another embodiment, the keratolytic agent is dithranol.In another embodiment, the keratolytic agent is salicylic acid. Inanother embodiment, the keratolytic agent is selenium disulfide. Inanother embodiment, the keratolytic agent is selenium sulfide. As usedherein, the terms “selenium sulfide” and “selenium disulfide” are usedinterchangably to refer to the chemical compound having the formula SeS₂where the ratio of selenium to sulfur is approximately 1:2. In anotherembodiment, the keratolytic agent is zinc pyrithione. In anotherembodiment, the keratolytic agent is zinc L-pyrrolidone carboxylate.

In some embodiments, more than one keratolytic agent is used.

In some embodiments, administration of a keratolytic agent to a keratinobstruction results in proteolysis of desmosomes forming tight junctionsbetween keratinocytes. In some embodiments, administration of akeratolytic agent results in lysis, including the hydrolysis ofdisulfide bonds. In some embodiments, administration of a keratolyticagent reduces the production of keratin

One embodiment provides a method for treating MGD in a patient in needthereof by administering a topical composition comprising a keratolyticagent, wherein the keraloytic agent comprises benzoyl peroxide. In someembodiments, the composition comprises 2.5%, 5%, or 10% benzoylperoxide. In some embodiments, the composition comprising benzoylperoxide is a suspension, emulsion, cream, lotion, gel, or ointment. Insome embodiments, the composition comprising benzoyl peroxide is appliedas a thin layer to clean skin initially once daily on alternate days,and is then gradually increased up to twice daily as tolerance develops.

One embodiment provides a method for treating MGD in a patient in needthereof by administering a topical composition comprising a keratolyticagent, wherein the keratolytic agent is coal tar. In some embodiments,the composition comprises a 5% to 10% solution of coal tar. In someembodiments, the composition comprising coal tar is at least 5%, 6%, 7%,8%, 9%, 10% or greater solution of coal tar. In one embodiment, thecomposition comprising coal tar is a 1% ointment of crude coal tar. Insome embodiments, the coal tar inhibits excessive proliferation ofepidermal cells by reducing DNA synthesis and mitotic activity to normallevels.

One embodiment provides a method for treating MGD in a patient in needthereof by administering a topical composition comprising a keratolyticagent, wherein the keratolytic agent is dithranol. In some embodiments,the composition comprises a 0.1% to 2.0% ointment of dithranol. In someembodiments, the composition comprising dithranol is at least 0.1, 0.2%,0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%,1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0, or greater of dithranol. In someembodiments, the composition comprising dithranol is started as a 0.1%ointment. After 7 days, the concentration may be increased to 0.25% andsubsequently doubled, if necessary, at weekly intervals to a maximumstrength of 2%. In some embodiments, a thin layer of ointment is appliedonce daily to the affected areas for 2-4 weeks. In some embodiments, theointment is left in place for 10 to 20 minutes before the area is rinsedthoroughly. In some embodiments, the dithranol slows epidermal celldivision and inhibits excessive proliferation and keratinization ofepidermal cells in patients.

One embodiment provides a method for treating MGD in a patient in needthereof by administering a topical composition comprising a keratolyticagent, wherein the keratolytic agent is salicylic acid. In someembodiments, the composition comprises 0.1% to 6% salicylic acid. Insome embodiments, the composition comprises at least 0.1%, 1%, 2%, 3%,4%, 5%, 6% or greater salicylic acid. In some embodiments, thecomposition comprising salicylic acid is an ointment or paste. In someembodiments, the composition comprising salicylic acid is appliedinitially as a thin layer of 2% ointment or paste, and is applied daily.In some embodiments, the concentration is gradually increased to amaximum of 5%, and treatment is continued for as long as necessary.

One embodiment provides a method for treating MGD in a patient in needthereof by administering a topical composition comprising a keratolyticagent, wherein the keratolytic agent is selenium disulfide. In someembodiments, the composition comprises 0.1% to 10% selenium disulfide.In some embodiments, the composition comprises at least 0.1%, 0.2%,0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%,1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, orgreater selenium disulfide. In some embodiments, the compositioncomprising selenium disulfide is a semi-solid. In some embodiments, thecomposition comprising selenium disulfide is a lotion. In someembodiments, the composition comprising selenium disulfide is a cream.In some embodiments, the composition comprising selenium disulfide is anointment. In some embodiments, the composition comprising seleniumdisulfide is a suspension. In some embodiments, the compositioncomprising selenium disulfide is a solution. In some embodiments thecomposition containing selenium disulfide enhances lipid production fromthe meibomian glands.

In some embodiments, the composition comprises inorganic seleniumcompounds that are inhibitors of prostaglandin synthase, the enzymeinvolved in the production of prostaglandins. The selenium compoundsdemonstrating this inhibitory effect include SeCl₄ and Na₂SeO₃. It isknown that the proinflammatory action of prostaglandins enhanceskeratinization and therefore these water-soluble inorganic seleniumcompounds that interfere with the production of prostaglandin may beuseful in reducing keratinization.

In some embodiments, the composition comprises organo-seleniumcompounds. Organo-selenium compounds such as Ebselen are antioxidant andanti-inflammatory agents inhibiting cyclooxygenase and lipooxygenaseenzymes and acting as scavenger of hydrogen peroxide as well ashydroperoxides including membrane bound phospholipid andcholesterylester hydroperoxides. Antiinflammatory agents are known toinhibit keratinization and therefore ebselen and other organo-seleniumanalogues may act as keratolytic agents through thisantioxidant/anti-inflammatory activity.

In some embodiments, the formulation comprising the keratolytic and/orkeratoplastic agent further includes an additional therapeutic agentthat is not a meibomian gland opening pharmacological agent. In someembodiments the formulation does not contain jojoba wax or jojobaextract. In some embodiments the formulation does not include boricacid. In some embodiments, the formulation does not include retinoicacid. Alternatively, in some embodiments, the formulation with thekeratolytic and/or keratoplastic agent excludes any additionaltherapeutic agent, other than an optional additional meibomian glandopening pharmacological agent.

Local Anesthetics

One embodiment provides a method for treating MGD in a patient in needthereof comprising topical administration of a composition comprising ameibomian gland opening pharmacological agent, wherein the meibomiangland opening pharmacological agent is a local anesthetic. In someembodiments, the meibomian gland opening pharmacological agent is alocal anesthetic chosen from an aminoamide local anesthetic, or anaminoester local anesthetic.

The term “local anesthetic” as used herein refers to an agent thatinduces a reversible absence of pain sensation. In some embodiments, alocal anesthetic may also induce temporary muscle paralysis in additionto inducing a reversible absence of pain sensation.

The local anesthetic agents described herein are useful primarily as anacute therapy, e.g., under the guidance of a physician or other trainedspecialist. The agents are tested, in certain embodiments, using theassays and methods described herein (e.g., as described in theexamples).

In some embodiments, the local anesthetic is an aminoamide. In someembodiments, the local anesthetic is an aminoester. In some embodiments,the local anesthetic comprises a combination of two or more localanesthetics. In some embodiments, the combination comprises anaminoamide local anesthetic and an aminoester local anesthetic.

In some embodiments, the local anesthetic is an aminoester selected fromthe group consisting of: benzocaine, chloroprocaine, cocaine,cyclomethycaine, dimethocaine, larocaine, piperocaine, propoxycaine,procaine, novocaine, proparacaine, tetracaine, and amethocaine.

In some embodiments, the local anesthetic is an aminoamide selected fromthe group consisting of: articaine, bupivacaine, cinchocaine, dibucaine,etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine,prilocaine, ropivacaine, trimecaine.

In some embodiments, the local anesthetic is a combination of lidocaineand prilocaine or a combination of lidocaine and tetracaine.

In some embodiments, the local anesthetic is a naturally derived localanesthetic. In some embodiments, the naturally derived local anestheticis selected from the group consisting of: saxitoxin, neosaxitoxin,tetrodotoxin, menthol, eugenol, and cocaine.

In some embodiments, the local anesthetic is mixed with avasoconstrictor to increase the duration of the local anesthesia byconstricting blood vessels. In some embodiments, priolocainehydrochloride is mixed with epinephrine. In some embodiments, lidocaine,bupivacaine are mixed with epinephrine. In some embodiments, iontocaineis mixed with lidocaine and epinephrine. In some embodiments, septocaineis mixed with a combination of articaine and epinephrine. In someembodiments, local anesthetic, bupivacaine or lidocaine are mixed incombination with a steroid.

Pharmaceutical Excipient

In other embodiments, the topical compositions described herein arecombined with a pharmaceutically suitable or acceptable carrier (e.g., apharmaceutically suitable (or acceptable) excipient, physiologicallysuitable (or acceptable) excipient, or physiologically suitable (oracceptable) carrier). Exemplary excipients are described, for example,in Remington: The Science and Practice of Pharmacy (Gennaro, 21^(st) Ed.Mack Pub. Co., Easton, Pa. (2005)).

Methods of Treatment Utilizing Meibomian Gland Opening PharmacologicalAgents

Described herein are methods for treating MGD in a patient in needcomprising topical administration of a meibomian gland openingpharmacological agent to the eyelid margin of the patient in need. Thereare two potential categories of administration. One occurs with theassistance of a health-care provider: this category includes both acuteand maintenance uses of the meibomian gland opening pharmacologicalagent. An acute use, in one embodiment, requires a stronger meibomiangland opening pharmacological agent (either in terms of concentration ofthe agent or the inherent activity of the agent). A maintenance use, inone embodiment, allows for the use of lower concentrations of the agent,or agents with lower inherent activity. A maintenance use, in oneembodiment, involves a patient at a routine visit to the health careprovider. Both acute uses and maintenance uses optionally involve use ofan eye-protecting device or apparatus. In one embodiment, the acute useis performed by the health care provider, and the maintenance use isperformed by the patient or non-health care provider. The secondpotential category of administration does not occur with the activeassistance of a health care provider, but rather involves the patientapplying the meibomian gland opening pharmacological agent to his/hereyelid margin. In one embodiment, such administration occurs over anextended period of time; one way of describing this patient-administeredmulti-administration mode is as a chronic use. In general, different orsecond formulations of the meibomian gland opening pharmacological agentare recommended for chronic or patient-administered uses. In oneembodiment the different or second formulation utilizes a lowerconcentration of the meibomian gland opening pharmacological agent. Inanother embodiment, the second or different formulation utilizes ameibomian gland opening pharmacological agent that has a lower activitythan the first formulation.

It should be understood that the present methods also include thephysical removal of the obstruction in the meibomian gland, followed bychronic and/or maintenance administration of the meibomian gland openingpharmacological agent described herein.

One embodiment provides a method for treating meibomian glanddysfunction in a patient in need thereof, comprising topicallyadministering to the patient a composition that reaches the eyelidmargin of the patient, wherein the composition comprises atherapeutically-effective amount of at least one keratolytic agent in anophthalmically-acceptable carrier. In some embodiments, the topicaladministration of the composition comprising a therapeutically-effectiveamount of at least one keratolytic agent in an ophthalmically-acceptablecarrier results in enhanced meibum production.

In some embodiments, the topical administration of the compositioncomprising a therapeutically-effective amount of at least onekeratolytic agent in an ophthalmically-acceptable carrier occurs untilthe keratinized obstruction is relieved. In some embodiments, thetopical administration of the composition comprising atherapeutically-effective amount of at least one keratolytic agent in anophthalmically-acceptable carrier occurs periodically after relieving ofthe keratinized obstruction. In some embodiments, the topicaladministration of the composition comprising a therapeutically-effectiveamount of at least one keratolytic agent in an ophthalmically-acceptablecarrier is a single administration. In some embodiments, the topicaladministration of the composition comprising a therapeutically-effectiveamount of at least one keratolytic agent in an ophthalmically-acceptablecarrier is a periodic administration. In some embodiments, the topicaladministration of the composition comprising a therapeutically-effectiveamount of at least one keratolytic agent in an ophthalmically-acceptablecarrier occurs once a day. In some embodiments, the topicaladministration of the composition comprising a therapeutically-effectiveamount of at least one keratolytic agent in an ophthalmically-acceptablecarrier occurs twice a day.

In some embodiments, the composition for topical administration,comprising a therapeutically-effective amount of at least onekeratolytic agent in an ophthalmically-acceptable carrier is asemi-solid. In some embodiments, the composition for topicaladministration, comprising a therapeutically-effective amount of atleast one keratolytic agent in an ophthalmically-acceptable carrier ishomogenous. In some embodiments, the composition for topicaladministration, comprising a therapeutically-effective amount of atleast one keratolytic agent in an ophthalmically-acceptable carrier is adispersion. In some embodiments, the composition for topicaladministration, comprising a therapeutically-effective amount of atleast one keratolytic agent in an ophthalmically-acceptable carrier ishydrophilic. In some embodiments, the composition for topicaladministration, comprising a therapeutically-effective amount of atleast one keratolytic agent in an ophthalmically-acceptable carrier hasan oleaginous base. In some embodiments, the composition for topicaladministration, comprising a therapeutically-effective amount of atleast one keratolytic agent in an ophthalmically-acceptable carrier hasat least one ophthalmically-acceptable excipient.

One embodiment provides a method for treating MGD in a patient in needthereof comprising topical administration of a composition comprising ameibomian gland opening pharmacological agent. In some embodiments, thetopical administration of the composition comprising a meibomian glandopening pharmacological agent occurs once a week. In some embodiments,the topical administration of the composition comprising a meibomiangland opening pharmacological agent occurs twice a week. In someembodiments, the topical administration of the composition comprising ameibomian gland opening pharmacological agent occurs every other day. Insome embodiments, the topical administration of the compositioncomprising a meibomian gland opening pharmacological agent occurs everyday. In some embodiments, the topical administration of the compositioncomprising a meibomian gland opening pharmacological agent occursseveral times a day.

In some embodiment, the method comprises treatment in an acute treatmentscenario. In another embodiment, the method comprises treatment of apatient naïve to treatment. In another embodiment, the method comprisestreatment in a chronic treatment scenario. In another embodiment, themethod comprises treatment in a maintenance therapy scenario. In anacute treatment scenario, the administered dosage of meibomian glandopening pharmacological agent maybe higher than the administered dosageof meibomian gland opening pharmacological agent employed in a chronictreatment scenario or a maintenance therapy scenario. In an acutetreatment scenario, the meibomian gland opening pharmacological agentmaybe different from the meibomian gland opening pharmacological agentemployed in a chronic treatment scenario. In some embodiments, thecourse of therapy begins in the initial phase of therapy as an acutetreatment scenario and later transitions into a chronic treatmentscenario or a maintenance therapy scenario. In some embodiments, themeibomian gland opening pharmacological agent administered in the acutetreatment scenario is a local anesthetic, and the meibomian glandopening pharmacological agent administered in the chronic treatmentscenario or a maintenance therapy scenario is a keratolytic agent and/orkeratoplastic agent. In some embodiments, the meibomian gland openingpharmacological agent administered in the acute treatment scenario is akeratolytic agent and/or keratoplastic agent, and the meibomian glandopening pharmacological agent administered in the chronic treatmentscenario or a maintenance therapy scenario is a keratolytic agent and/orkeratoplastic agent.

In certain clinical presentations, patients may require an initialtreatment administered by a physician or healthcare professional, toinitially open the blockage of the meibomiam gland, either by placing amore highly concentrated formulation of one of the therapeutic agentsdescribed herein. In the event the higher concentration formulations arerequired, the application thereof may require ocular shielding or otheractivity to minimize the impact of irritation or disruption of theocular surface or surrounding tissues. Following such a procedure, apatient may be given a different formulation of active agent to takehome to apply periodically to the lid margin to maintain the patency ofthe meibomiam gland. Such application may occur twice daily, once a day,weekly or monthly, depending on the formulation activity and the desiredproduct profile of the therapy.

One aspect of the methods of treatment described herein is the locationof the topical administration of the composition. In one embodiment, thecomposition comprising a meibomian gland opening pharmacological agentis administered such that no irritation to eye occurs. In oneembodiment, the composition comprising a meibomian gland openingpharmacological agent is administered to the eye lid margin.

One additional embodiments of the methods of treatment described hereinis the use of a protective element provided to the eye to avoidirritation to the eye. Although the formulations described herein aregenerally non-irritating, in some embodiments (e.g., high concentrationof agent or when used on a sensitive eye) a protective element providesan additional layer of safety and comfort for the patient. In oneembodiment, the composition comprising a meibomian gland openingpharmacological agent is administered while an eye shield is placed onthe eye to reduce contact of the pharmacological agent with the corneaand/or conjunctiva such that reduced irritation to eye occurs. In someembodiments, the eye shield is a contact lens or an eye covering. Insome embodiments, the eye covering comprises a self-adhesive. In oneembodiment, the composition comprising a meibomian gland openingpharmacological agent is administered while the lid is pulled away fromthe globe to reduce contact of the pharmacological agent with the corneaand/or conjunctiva such that reduced irritation to eye occurs.

Certain Definitions

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary between 1% and 15% of the stated number or numericalrange. The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, may “consist of” or “consist essentially of” thedescribed features.

The terms “treat,” “treating,” or “treatment” as used herein, includereducing, alleviating, abating, ameliorating, relieving, or lesseningthe symptoms associated with MGD in either a chronic or acutetherapeutic scenario. In one embodiment, treatment includes a reductionof a terminal duct obstruction.

The term “recurrence,” or “reducing relapse” refers to return of MGDsymptoms in a chronic therapeutic scenario.

The term “opening” refers to the clearing (at least in part) of anobstructed meibomian gland canal or orifice and/or maintaining thepatency of the meibomian gland canal or orifice.

The term “keratolytic agent” and/or “keratoplastic agent” as used hereinrefers to an agent that softens, disrupts, dissolves, solubilizes, orloosens a keratinized obstruction, or prevents the formation of akeratinized obstruction. Specifically, the term “Keratolytic agents”refers to agents used to promote softening and dissolution of keratinand the term “keratoplastic agents” refers to agents used to reducekeratin production.

The term “lotion” describes an emulsion liquid dosage form. This dosageform is generally for external application to the skin (US FDA DrugNomenclature Monograph, number C-DRG-00201).

The term “cream” describes an emulsion semisolid dosage form, usuallycontaining >20% water and volatiles and/or <50% hydrocarbons, waxes orpolyols as the vehicle. A cream is more viscous than a lotion. Thisdosage form is generally for external application to the skin (US FDADrug Nomenclature Monograph, number C-DRG-00201).

The term “ointment” describes a semisolid dosage form, usuallycontaining <20% water and volatiles and/or >50% hydrocarbons, waxes orpolyols as the vehicle. This dosage form is generally for externalapplication to the skin or mucous membranes (US FDA Drug NomenclatureMonograph, number C-DRG-00201).

The term “solution” describes a clear, homogeneous liquid dosage formthat contains one or more chemical substances dissolved in a solvent ormixture of mutually miscible solvents (US FDA Drug NomenclatureMonograph, number C-DRG-00201).

The term “suspension” refers to a heterogeneous mixture containing solidparticles that are sufficiently large for sedimentation.

EXAMPLES Example 1 Assessing Keratolytic Efficacy of Salicylic Acid,Benzoyl Peroxide, and Retinoic Acid

Keratolytic efficacy of an agent is optionally assessed by examiningstratum corneum (SC) tape strippings to measure the total SC proteinamount removed and on the tape. The amount of skin mass on the tape isdirectly proportional to the amount of keratolysis.

Salicylic acid is a keratolytic, while retinoic acid is known mostly forits comedolytic properties, and benzoyl peroxide is known mostly for itsanti-microbial mechanism. Here, all three were examined for relativekeratolytic efficacy.

The tape stripping results revealed that benzoyl peroxide haskeratolytic effects comparable to that of salicylic acid and retinoicacid. After 3 hours, benzoyl peroxide was significantly more effectivein interfering with SC cohesion than either salicylic acid or retinoicacid under the present conditions. After 6 hours of treatment, all threewere similarly effective. The SC removal by retinoic acid increased byapproximately 35% for 3-6 hours, as compared to about 10% for salicylicacid and benzoyl peroxide. Hence, retinoic acid's keratolytic propertiesafter prolonged application were comparable to benzoyl peroxide.

Example 2 Effect of Selenium Disulfide and Salicylic Acid on KeratinRemoval in Forearm and Eyelid

The objective of the study was to evaluate the effect of potentialkeratolytic agents on keratin removal as detected by lissamine greenremoval. Lissamine green stains keratin.

The following reagents were used for the study: 1% salicylic acid (SA),2.5% selenium disulfide (SD), diluted 1:10 selenium disulfide (SD/10),soap containing citric acid salicylic acid (SK), tearless shampoo (SS),and lissamine green (LG).

Study #1: Forearm A

LG stains keratin and was therefore used to evaluate the effectivenessof various agents on their ability to remove five keratin spots (2.5cm×2.5 cm) of LG. LG was applied to each forearm of both arms of 2subjects. Each spot was compared to the contralateral spot in thecontralateral forearm. Different substances were administered over theLG spot.

The following comparison spots were analyzed: SA vs. control; SA vs. SK;SA vs. SD; SD vs. control; SD vs. SK.

Ten minutes following application, gentle scrubbing (×10) wasadministered to each spot using a golf club spud in order to evaluatethe LG removal. Lissamine color intensity was compared between each pairto evaluate the degree of LG removal (better removal=less LG remnant wasdefined as superior).

The results were identical in both subject and superiority in removal ofkeratin. SA>control; SA<SK; SA<SD; SD>control; SD roughly equal to SK.

Study #2: Forearm B

Three spots (2.5 cm×2.5 cm) of lissamine green (LG) application weredone in each forearm of one subject. Each spot was compared to thecontralateral spots in the contralateral forearm. Different substanceswere administered over the LG spot. The following comparisons wereanalyzed: SS vs. SK; SD vs. SD/10.

Ten minutes following application, gentle scrubbing (×10) wasadministered to each spot using a golf club spud in order to evaluatethe degree of LG removal.

The results were as follows: SS<SK; SD>SD/10

Study #3: Forearm C

Four spots (2.5 cm×2.5 cm) of lissamine green (LG) application wereapplied to the forearm of one subject. SK was applied for: 10 minutes, 5minutes, 3 minutes, 2 minutes, and 1 minute.

At the end of each period, a gold club was used to scrape (×10) thematerial.

After 10 and 5 minute application, the SK almost completely removed thekeratin. The three minute application of SK resulted in good removal ofkeratin. The two minute application of SK was suboptimal in removingkeratin. The 1 minute application was unsatisfactory in removingkeratin.

Study #4: Eyelid A

The goal of this study was to investigate the tolerability of SD appliedto the eye of a subject. A light layer of SD was applied to the lowerlid in one subject. The application of SD resulted in immediate severeirritation. The eye was washed immediately. Irritation and red eyepersisted for about 30 minutes and then subsided.

Study #5: Eyelid B

LG was applied to the lower eyelid of one subject. Because SD isirritating to the eye, safety precautions were taken. The anteriorsurface of the eye was protected by placing a contact lens over corneafollowed by anesthesia drops and pulling of the eyelid away from theglobe while SD was present on the eyelid. SD was applied on the centralpart of the eye lid while the nasal and temporal parts were left onlywith the LG stain. Ten minutes following application, gentle scrubbing(×2) with a sponge tip was performed to the entire lower eyelid.

LG staining was completely removed in the central part that was treatedwith SD and was not removed in the temporal or nasal areas that were nottreated. During the procedure some stinging was felt, but was tolerableto the subject. No adverse events occurred.

Study #6: Eyelid C

LG was applied to the lower lid. SD was applied on the nasal third ofthe lid, SD/10 was applied on the temporal third, and the middle thirdwas left only with the LG stain. Ten minutes following application,gentle scrubbing (×2) with a sponge tip was performed to the lowereyelid.

The LG staining was completely removed in the nasal third that wastreated with SD. LG staining was not removed in the central third thatwas not treated. LG staining was slightly removed to the temporal thirdthat was treated with SD/10. The procedure was uneventful, slightburning was felt on nasal side (non-diluted SD), but not on the temporalside (diluted SD).

Conclusion of Studies 1-6.

The results demonstrated the following:

1) Selenium disulfide (2.5% preparation) is highly irritable to the eyeand cannot be applied without substantial precaution to avoid mucosaland corneal touch and the use of topical anesthesia.

2) The presumed effectiveness scale was as followed (most effective tonot effective): (SD=SK)>(SD/10)=(SA)>(SS)>(control).

3) Soap alone (the detergent) is not sufficient for removing thekeratin.

4) Selenium disulfide and the SK soap were found to have the same effecton skin keratin removal. Note that the SK soap contains a couple ofkeratolytic agents (salicylic acid and possibly citric acid) withunknown concentrations.

5) The duration of SK application is important in determining itseffect.

6) Selenium disulfide is highly effective in removing keratin from theeyelid.

7) The diluted 1:10 selenium disulfide was found to be significantlyless effective in the forearm skin keratin removal compared to thenon-diluted SD (2.5%).

8) The diluted 1:10 selenium disulfide was found to be less effective inthe lid keratin removal compared to the non-diluted SD (2.5%) but betterthan control.

Example 3 17 Day Study of Selenium Disulfide 2.5% Treatment Over EyelidMargins in Patients with MGD

A novel observation of use of selenium disulfide was also observed,giving rise to the novel hypothesis that at least one agent active agentis effective in pharmacologically treating the obstruction in themeibomian gland, without the need for additional mechanicalintervention.

Eight patients with meibomian gland disease with signs and symptoms ofdry eye, were treated in one of their eyes for 17 days, twice a week (5total applications) with a commercially available suspension comprising2.5% selenium disulfide. The suspension was placed over the treatedeyelid margin for 5 minutes. The fellow eye was not treated and servedas a control. After 5 treatment sessions in which 2.5% seleniumdisulfide suspension was applied to the eyelid margin, dry eye signs andsymptoms improved significantly compared to the fellow control eyes.Results of the eight patients who underwent 2.5% selenium disulfidetreatment are shown in Table 1.

TABLE 1 Assessment of MGD and dry eye symptoms in patients treated witha 2.5% selenium disulfide suspension for 17 days Control Treated Eye EyeBase- (untreated) Assessment line Day 17 pValue Baseline Day 17 pValueSPEED 12.00 7.88 0.01 11.88 9.38 0.11 question- naire TBUT (sec.) 7.3816.81 0.004 10.91 12.00 0.65 Number 2.75 6.25 0.02 3.63 3.13 0.71 ofopen meibomian gland on digital expression

Example 4 Effect of High Concentration Topical Anesthetic Cream(Lidocaine 23% and Tetracaine 7% Ointment) Treatment

A study in which mechanical expression and probing was were compared wasconducted. Since both methods are painful to the patient high dosetopical anesthesia (Lidocaine 23% and Tetracaine 7% Ointment) notindicated for ocular use was applied of the lids prior to eitherprocedures. The topical anesthesia was not removed from the eyefollowing its application. A novel observation of an additionalmechanism of anesthetic was also observed, giving rise to the novelhypothesis that at least one agent active agent is effective inpharmacologically treating the obstruction in the meiboiam gland. In acertain set of cases, local anesthetic agent was observed to have a fulltherapeutic benefit in alleviating gland obstruction without the needfor further mechanical intervention and separate from nominallyproviding comfort to assist in the mechanical extraction of glandcontent.

Two patients with MGD were treated topically to the lower lids of botheyes with a 23% lidocaine and 7% tetracaine cream applied 2-3 times. Thecream was not removed from the eyelids. Probing was done to one eye,while expression was done to the fellow eye. Probing was successful inboth patients. Expression was partially successful in one patient(expressible material came from about 50% of glands) and no expressiblematerial came from the eye of the other patient (e.g. the glands werecompletely blocked). A few hours after the procedure, both patientspresented with corneal abrasions that were likely caused by theanesthetic cream.

After 48 hours, both patients were examined again. The patient that hadthe complete blockage (patient #2) demonstrated dramatic (50%)improvement in his meibomian gland function (a combination of number ofopen glands and quality of meibum) (improvement of MG score from 96 to52) with clear meibum present following light digital expression in manyglands. The other patient (patient #1) showed about 25% improvement(score improved from 46 to 36). The results of patients 1 and 2 areshown in Table 2.

Nine other patients were treated using lidocaine 4% ophthalmic gel. Inthese cases where meibomian gland blockage was present, no improvementin meibomian gland function was observed.

TABLE 2 Treatment of patients 1 and 2 with 23% lidocaine and 7%tetracaine ointment followed by meibomian gland expression or probing.48 hours Post Baseline Treatment Patient Combined Combined Number GenderAge MG score* MG score* 1 F 71 48 36 2 M 63 96 42 *Each MG is assigned anumber based on outcome of expression where 0 = clear meibum, 1 =whitish meibum, 2 = yellow thicker meibum, 3 = paste like meibum, and 4= total obstruction. This number is multiplied by the number of glandsobserved. The higher the number, the more severe the obstruction.

Example 5 Effect of High Concentration Topical Anesthetic Cream(Lidocaine 23% and Tetracaine 7% Ointment) Treatment on Meibomian GlandPatency

Four patients with MGD were treated with high dose topical anesthesia(Lidocaine 23% and Tetracaine 7% Ointment) not indicated for ocular useon the lower eyelid margins only. The eyelid was pulled away from theglobe and was taped to the lower cheek for 15 minutes to avoid directcontact between the medication and the anterior surface of the eye. Acontact lens was also placed as a barrier for the drug in case someleaks towards the globe High concentration topical anesthetic cream wasapplied as a thin layer and was wiped off after 15 minutes. Theprocedure did not cause any adverse events. The results are listed belowin Table 3. In patient #6, significant meibomian gland functionimprovement was observed. A doubling of the tear meniscus height wasmeasured using Oculus M5 Kertometer in the study eye and no change wasobserved in the fellow eye. In all other patients, no change in MG scoreof tear meniscus in either eye was observed. It is noted that while inexample 5 the high concentration topical anesthesia was left on the lidand was not wiped off, in this group of patients it was wiped off after15 minutes.

TABLE 3 Treatment of patients with Telica (23% lidocaine and 7%tetracaine ointment) and the effect on meibomian gland patency. 48 hoursPost Baseline Treatment Tear Combined Patient Gen- Tear Combinedmeniscus MG Number der Age meniscus MG score* (M5) score* 3 M 67 0.37 880.39 78 4 F 58 0.29 96 0.25 88 5 F 68 0.32 93 0.33 90 6 F 62 0.4 92 0.7148

1. A method for treating meibomian gland dysfunction in a patient in need thereof, comprising topically administering to the patient a composition that reaches the eyelid margin of the patient, wherein the composition comprises a therapeutically-effective amount of at least one keratolytic agent in an ophthalmically-acceptable carrier, wherein the keratolytic agent is an inorganic selenium compound, or an organo-selenium compound.
 2. The method of claim 1, wherein the keratolytic agent is an inorganic selenium compound.
 3. (canceled)
 4. The method of claim 2, wherein the inorganic selenium compound is selenium disulfide.
 5. The method of claim 4, wherein the concentration of the selenium disulfide in the composition is between about 0.1% to about 10%.
 6. (canceled)
 7. (canceled)
 8. The method of claim 1, wherein composition is topically administered to the patient until the keratinized obstruction is relieved.
 9. The method of claim 1, wherein composition is topically administered to the patient periodically after relieving the keratinized obstruction.
 10. The method of claim 1, wherein the topical administration is a single administration.
 11. The method of claim 1, wherein the topical administration is a periodic administration.
 12. The method of claim 11, wherein the periodic administration is once a day.
 13. The method of claim 11, wherein the periodic administration is two times a day.
 14. The method of claim 1, wherein the composition for topical administration is a semi-solid.
 15. The method of claim 1, wherein the composition for topical administration is homogenous.
 16. The method of claim 1, wherein the composition for topical administration is a dispersion.
 17. The method of claim 1, wherein the composition for topical administration is hydrophilic.
 18. The method of claim 1, wherein the composition for topical administration has an oleaginous base.
 19. The method of claim 1, wherein the ophthalmically-acceptable carrier comprises at least one ophthalmically-acceptable excipient.
 20. The method of claim 1, wherein the administration of the composition results in enhanced meibum production.
 21. A method for treating meibomian gland dysfunction in a patient in need thereof, comprising topically administering to the patient a composition that reaches the eyelid margin of the patient, wherein the composition consists of a therapeutically-effective amount of a keratolytic agent in an ophthalmically-acceptable carrier, wherein the keratolytic agent is an inorganic selenium compound, or an organo-selenium compound.
 22. The method of claim 21, wherein the keratolytic agent is an inorganic selenium compound.
 23. The method of claim 22, wherein the inorganic selenium compound is selenium disulfide.
 24. The method of claim 23, wherein the concentration of the selenium disulfide in the composition is between about 0.1% to about 10%.
 25. The method of claim 21, wherein the administration of the composition results in enhanced meibum production.
 26. The method of claim 21, wherein the composition for topical administration is homogenous.
 27. The method of claim 21, wherein the composition for topical administration is a dispersion.
 28. The method of claim 21, wherein the composition for topical administration is hydrophilic.
 29. The method of claim 21, wherein the composition for topical administration has an oleaginous base.
 30. The method of claim 21, wherein the ophthalmically-acceptable carrier comprises at least one ophthalmically-acceptable excipient. 